The overall objectives of our research are to determine what role, if any, nitrite and nitroso compounds play in the etiology of human cancer. The main focus of the Program will be concerned with exploring and testing the hypothesis that endogenous factors are important in either causation or modification of the process of carcinogenesis in humans. Project 1 will investigate how different types of cells make nitric oxide from arginine. Nitric oxide is the reactant which yields the nitrosating agents N2O3 and N2O4 in the presence of O2. Project 2 proposes several animal models in which infectious agents lead to increased risk of cancer. Both gastric cancer and liver cancer will be investigated as models in which nitrogen oxides may play a role. Project 3 will investigate the role of somatic mutations in ras genes, the inactivation of the P53 gene and the occurrence of the TPR-MET oncogene rearrangement in experimental gastric carcinogenesis. Project 4 will investigate the pharmacokinetics of dimethylamine and trimethylamine; the aqueous chemistry of nitric oxide; and the formation of nitrosamines from nitric oxide. Project 5 will examine the chemistry of indole nitrosation products and their reactions with DNA and the potential for reactions between nitrogen oxides and DNA. Each project explores basic mechanisms of endogenous carcinogenesis and the Program as a whole may lead to new directions in the prevention of cancer.